11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine, which is named Quetiapine, is an antipsychotic, and expressed by the following Formula 1.
Formula 1

A representative process of producing 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine is as follows.
EP 240228 B1 discloses a production process in which 1-(2-hydroxyethoxy)ethylpiperazine reacts with an imino chloride compound expressed by the following Formula 2.

Meanwhile, the imino chloride compound, which is expressed by the above Formula 2, is produced by reacting 10H-dibenzo[b,f][1,4]thiazepine-11-on, which is expressed by the following Formula 3, with phosphorus oxychloride (POCl3) (Helv. Chim Acta, 50, 245 (1967)).

The 10H-dibenzo[b,f][1,4]thiazepine-11-on having the above Formula 3 is produced by reacting 2-aminodiphenyl sulfide reacts with phenylester chloroformate so as to produce phenyl 2-(phenylthio)phenyl carbamate, and then conducting a cyclization reaction in the presence of polyphosphoric acid.
However, in the above-mentioned production process, an excessive amount of polyphosphoric acid is used as a solvent, causing the generation of an excessive amount of acidic wastewater, resulting in harmful effects to the environment. Additionally, a lot of heat is generated when dilution is conducted using water in an end stage of the reaction, thus it is difficult to commercially produce it.
Furthermore, purification must be conducted using column chromatography in order to produce highly pure 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine of the above Formula 1, resulting in economic inefficiency.
As well, since the imino chloride compound of the above Formula 2 is unstable and is thus readily hydrolyzed due to moisture in air, there are many problems in the course of separating, purifying, and storing it. Particularly, in a commercial production process using a great amount of the compound, undesirably, hydrolyzed impurities are contained in final goods, thus reducing purity of the goods.
EP 282236 B1 discloses a method of producing 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine through a reaction of 11-piperazinyl-dibenzo[b,f][1,4]thiazepine of the following Formula 4 with 2-chloroethoxyethanol.

However, since the method employs the same intermediate as in the above-mentioned EP 240228 B1, it is disadvantageous in that it is difficult to achieve commercial production because of a lot of acidic wastewater generated by the use of an excessive amount of polyphosphoric acid and heat emission. Additionally, there are many problems in the method, for example, hydrolysis occurs due to cleavage of the unstable imino chloride compound of Formula 2.
According to WO 0155125, 2-aminodiphenyl sulfide reacts with phenylester chloroformate to produce phenyl 2-(phenylthio)phenyl carbamate, and N-[4-(2-chloroethyl)piperazine-1-aminodiphenyl sulfide is produced through a reaction using hydroxyethylpiperazine and another reaction using thionyl chloride. The resulting product, then, reacts with phosphorus oxychloride and phosphorus pentoxide to produce 11-[4-(2-chloroethyl)-1-piperazinyl]-dibenzo[b,f][1,4]thiazepine, and then reacts with ethylene glycol to produce 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.
However, phosphorus oxychloride, which is used as a reaction solvent in the production method, generates a lot of acidic waste, and phosphorus pentoxide is difficult to handle because it is unstable in air and is highly corrosive and toxic, thus it is difficult to achieve commercial production. As well, sodium metal, which is used as a base in a reaction with ethylene glycol, is highly combustible and explosive, thus it is difficult to achieve commercial production.